There has been tremendous interest in the development of GLP-1-based analogues as well as exendin-based GLP-1R agonists for the treatment of diabetes. This section of glucagon.com will briefly highlight some of the early results of these studies however there is now an extensive independent clinical trial literature for exenatide, liraglutide, albiglutide, lixisenatide and dulaglutide.
Six week infusion of native GLP-1 in Type 2 Diabetes
Native GLP-1 has been infused by the subcutaneous route (4.8 pmol/kg/min) using a portable insulin pump in a non-randomized study of subjects with Type 2 diabetes over the age of 40 (mean age 55) with mean initial HbA1c of about 9%, and mean fasting glucose ~14 mM. Oral antidiabetic medication was discontinued 3 weeks prior to the study. In GLP-1-infused subjects, plasma levels of GLP-1 rose from ~ 19 pM to 197 pM by week 1, and 282 pM at week 6. Six weeks of GLP-1 infusion resulted in significant improvements in fasting (decrease of 4.3 mM glucose) and 8 h mean glucose (decrease of 5.5 mM), fasting and mean 8h free fatty acids, a reduction in HbA1c from 9.2% to 7.9%, a decrease in fructosamine from 349 uM to 282 uM, and a reduction in gastric emptying.
Multiple parameters of beta cell function, including C-peptide responses to glucose and arginine improved in the GLP-1-treated patients. See Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002 Mar 9;359(9309):824-30
Twelve week infusion of GLP-1 in elderly subjects
A clinical trial of native GLP-1 was carried out in 16 patients with type 2 diabetes treated with oral hypoglycemic agents. Eight patients (aged 75 +/- 2 years, BMI 27 +/ 1 kg/m(2)) continued on their usual glucose-lowering therapy and eight patients (aged 73 +/- 1 years, BMI 27 + 1 kg/m(2), discontinued their hypoglycemic medications and received GLP-1 by continuous subcutaneous infusion, at varying doses, for 12 weeks. Primary end points were HbA(1c) and blood glucose determinations. HbA(1c) levels (7.1%) and body weight were equally maintained in both groups however the GLP-1-treated group had much less hypoglycemia. GLP-1 enhanced glucose-induced insulin secretion and insulin-mediated glucose disposal. See Effects of 3 Months of Continuous Subcutaneous Administration of Glucagon-Like Peptide 1 in Elderly Patients With Type 2 Diabetes. Diabetes Care. 2003 Oct;26(10):2835-2841
NN2211, subsequently renamed Liraglutide (Victoza), is an acylated albumin-bound human GLP-1 analog that exhibits a prolonged duration of action in preclinical rodent studies. For information on studies with this GLP-1R agonist, see Liraglutide
Exendin-4, subsequently renamed Exenatide, is a naturally occurring DP IV-resistant GLP-1 analog, lizard exendin-4, has been examined in both short term and more prolonged administration regimens in man. To review basic studies and preclinical investigation, see Exendin-4
For an overview of the Exendin-4 data in man, see Exendin-4: Human data
CJC-1131: GLP-1-albumin drug affinity complex (DAC) technology. GLP-1 is a GLP-1 analogue engineered for covalent coupling to albumin. The GLP-1 albumin compound retains the ability to bind to and activate the GLP-1 receptor, and appears to exhibit highly similar biological actions, compared to native GLP-1, when assessed using cells in vitro, or rodents in vivo. For an overview of CJC-1131, see Development and characterization of a glucagon-like Peptide 1-albumin conjugate: the ability to activate the glucagon-like Peptide 1 receptor in vivo. Diabetes. 2003 Mar;52(3):751-9. The development of CJC-1131 has been discontinued.
Albiglutide, originally referred to as Albugon, is a recombinant human albumin-GLP-1 protein that mimics all of the known GLP-1 actions through the GLP-1 receptor that a small peptide does, despite its much larger size and complex structure A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes. 2004 Sep;53(9):2492-50. Analysis of the pharmacokinetic properties of Albiglutide from 9-64 mg, in human subjects demonstrates sustained levels of circulating protein following single injections in vivo, suggesting the possibility of once weekly dosing for this molecule Pharmacodynamics, Pharmacokinetics, Safety and Tolerability of Albiglutide, a Long-Acting GLP-1 Mimetic, in Patients With Type 2 Diabetes. J Clin Endocrineol Metab. 2008 Sep 23. [Epub ahead of print]. An escalating dose study in non-diabetic subjects examined the PK profile of albiglutide at doses ranging from 0.25 to 104 mg given 1 week apart. The results suggest that albiglutide likely can be administered once weekly, and possibly less frequently. See Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects Diabetes Obes Metab. 2009 Feb 2. [Epub ahead of print]
The Phase 3 clinical trial program for albiglutide (Syncria) was commenced in early 2009, and culminated in the approval of Albiglutide for the treatment of diabetes in 2014 in the USA. Most of the studies used 30 mg once weekly albiglutide dose for the majority of arms, however 50 mg once weekly was also studied..
ZP10, Zealand Pharma, and Aventis
ZP10 is an exendin-4 derivative being developed by Zealand Pharmaceuticals. A licensing deal with Aventis was announced on June 25 2003, whereby Aventis received global rights to and responsibility for commercialization of ZP10 (AVE-0010). See the Zealand Press Release and the Sanofi update of AVE-0010 Phase 2 Data from Septmber 2007 Lyxumia ELIXA CVS outcomes studies
Roche, Beaufour Ipsen and (BIM51077) Taspoglutide
BIM51077 is a human GLP-1 derivative, originally developed and taken through Phase 1 studies by Ipsen, now licensed to Roche, as outlined in their Oct 21 2003 Press Release. Subsequently renamed Taspoglutide, this once weekly GLP-1R agonist entered Phase 3 clinical trials for the treatment of T2DM. Phase 2 analysis of Taspoglutide efficacy was assessed in human subjects with T2DM not achieving adequate glycemic control on metformin alone. Patients received 5, 10, or 20 mg once weekly, or 10 or 20 mg Taspoglutide every other week. The duration of therapy was 8 weeks. Taspoglutide produced significant reductions in HbA1c and body weight, with GI side effects the most common AEs reported Treatment with the human once-weekly GLP-1 analogue taspoglutide in combination with metformin improves glycemic control and lowers body weight in patients with type 2 diabetes mellitus inadequately controlled with metformin alone: a double-blind placebo-controlled study Diabetes Care. 2009 Apr 14. [Epub ahead of print] . The efficacy of Taspoglutide was evaluated in a comprehensive Phase 3 Program. The T-emerge Phase III clinical trial programme, designed as multicenter, multi-country, randomized, controlled (active or placebo), double-blind and open studies. Over 6000 patients will be enrolled in the eight studies that comprise the T-emerge programme. Studies include two parallel taspoglutide arms including 10 mg once weekly and 10 mg once weekly titrated up to 20 mg once weekly after 4 weeks. Four of the eight studies have active comparators, including exenatide, sitagliptin, insulin glargine and pioglitazone. Interim top line results from the Taspoglutide T-Emerge studies have been presented periodically in 2010. Taspoglutide development was discontinued due to emergence of rare allergic reactions, including several cases of mild anaphylaxis.
LY315902 is a Lilly DPP-IV-resistant GLP-1 analogue and LY307161 SR is a sustained release formulation of a GLP-1 analog suitable for once daily administration; LY307161 efficacy has been examined in human clinical trials. In data presented at the 2002 ADA Meeting in San Francisco, the pharmacokinetic/-dynamic effects of a single 4.5 mg LY307161 SR was evaluated in 9 patients with Type 2 diabetes, mean age 60, BMI 30.3, HbA1c 7.3, treated with diet (7) and/or metformin (2) over a period of 21 days. Food intake on test days was identical for each individual. In all but one patient, blood glucose was lowered to near-normal levels throughout the duration of the test days (day 6 and day 21). No hypoglycemia was observed and the average body weight of the patients declined by 2.1 + 0.5 kg. Nevertheless, Eli Lilly announced it was discontinuing the GLP-1 analogue clinical program at the time it disclosed its intent on Friday Sept 20 2002 to partner with Amylin in the clinical development of exendin-4 (AC2993-Exenatide).
On December 11 2008, Lilly provided further information about 2 distinct GLP-1 molecules in the clinic, a Fc immunoglobulin fusion protein LY2199265 (Dulaglutide) , and a pegylated GLP-1 molecule LY2428757. See Lilly GLP-1 analogues. The top line results of the AWARD Dulaglutide clinical trial program have been disclosed by press release and subsequently published. Dulaglutide, a once weekly GLP-1R agonist, was approved in the United States (see Dulaglutide/Trulicity PI) on September 17 2014.
To review safety issues surrounding use of GLP-1R agonists to treat diabetes, see GLP-1: Adverse Events